Herpes simplex virus (HSV) keratitis is a leading cause of non-traumatic blindness in developed countries, with more than 200,000 cases per year in the USA. HSV can cause a variety of ocular diseases in humans ranging from self-limiting dendritic epithelial keratitis, conjunctivitis, and blepharitis to necrotizing stromal keratitis. In addition, HSV commonly causes cold sores, genital sores, and is a leading cause of viral encephalitis. The life cycles of HSV and other neurotropic herpesviruses are characterized by a lytic phase of infection at peripheral sites such as the cornea and skin during which all virus genes are expressed, and a latent phase in neurons, during which gene expression is extremely limited. Latency represents a lifelong source of virus which reactivates periodically causing severe ocular and other damage. The ability of HSV to establish lifelong latency renders it resistant to cure and represents a major hurdle in the prevention of herpetic diseases, the majority of which result from reactivation from latency. Xenophagy is an important PKR-dependent host defense mechanism against chronic intracellular pathogens. It is a subset of the constitutive cellular process known as autophagy (self-eating), in which cytoplasmic components are sequestered and degraded by the lysosome to generate metabolic precursors, to remove damaged organelles and altered intracellular components. If the autophagic vacuole also engulfs and destroys invading pathogens, the process is known as xenophagy. Typical of many microbial countermeasures against innate immunity, xenophagy is either inhibited by the invading pathogen, or alternatively exploited to enhance its replication cycle. The processes of autophagy and xenophagy and their alteration by microbes is therefore another component of the cat-and-mouse game of microbial pathogenesis and host-pathogen interactions. A better understanding of these autophagic/xenophagic pathways could lead to a whole new class of antiviral therapies, designed to augment the xenophagic degradation of otherwise hard-to-treat intracellular pathogens, or to deny certain pathogens access to the autophagic machinery which serves to promote their replication. Three important aspects of the pathogenesis of HSV will be studied in this application. First, the role of xenophagy will be determined in several stages in the pathogenesis of HSV-1. Second, viral genes that subvert the host innate xenophagy and interferon (IFN)-mediated antiviral responses will be studied. Third, the role of this subversion will be studied in pathogenesis in the cornea and other tissues critical for HSV pathogenesis. The interplay of viral and host factors at various stages in the virus lifecycle remains poorly understood. A better understanding, at the molecular level, of factors involved in HSV pathogenesis is in accordance with stated research goals of the December 2006 National Plan for Eye and Vision Research.